Cancer immunotherapy trials conducted with the best available science resulted in anecdotal responses such that the field of cancer immunotherapy did not quite succeed fulfilling the great hopes of conquering cancer and began to lose credibility (Allison, JAMA, 1113-1115 (2015)). In contrast, studies initiated by James P. Allison led to a breakthrough via the immune checkpoint (IC) blockade (Postow et al., J Clin Oncol, 33, 1974-1982 (2015)).
While the CTLA-4 blockade interrupted T cell pathways responsible for immune down-regulation and mediated regression of established malignant tumors in a minority of patients, this has to be weighed against the immune-related adverse events (irAEs) suffered by the majority. The data from 14 completed phase I-III trials of ipilimumab indicated that irAEs occurred in 64.2% of patients. Life-threatening side effects, pathognomonic of acute graft-versus-host-disease (GVHD) and drug-related deaths (<0.1%) have been reported in most trials (Graziani et al., Pharmacological Research, 65, 9-22 (2012)) (Voskens et al., PLoS. ONE., 8, e53745-(2013)) (Shih et al., Drugs, 74, 1993-2013 (2014)). An interesting and consistent observation is that a higher incidence of irAEs, particularly grade 3/4 irAEs, has been associated with a higher proportion of patients eventually achieving an objective response (Attia et al., J Clin Oncol, 23, 6043-6053 (2005)). An increase in the immune-related adverse events is dependent upon the doses (irAEs of any grade 70%, 65%, and 26% of patients at doses of ipilimumab (anti-CTLA-4 antibody) of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg respectively); in the 10 mg/kg patient group, a quarter of the patients suffered grade 3-4 events (Robert et al., Oncologist., 14, 848-861 (2009)). In this context, we addressed the safety-efficacy problem in ipilimumab trials, which is still an unresolved and timely issue in oncology (Bakacs et al., Immunobiology, 217, 583-589 (2012)) (Bakacs et al., Pharmacol. Res., 66, 192-197 (2012)) (Slavin et al., Pharmacol. Res. (2013)) (Bakacs et al., Immunobiology, 220, 624-625 (2014)).
The instant invention suggests a therapeutic paradigm shift, which may help break the impasse. This is based on two groundbreaking but neglected proof-of-principle papers that demonstrated augmented graft-vs.-malignancy (GVM) effect that reversed the relapse of malignancy without worsening the graft-vs.-host disease (GVHD) by a CTLA-4 blockade. The task, in the inventors' view, is not trying to increase dosages of immune-suppressive steroid treatments, but harnessing the immense forces liberated by the anti-CTLA-4 antibody blockade by pre-targeting or dose adjustments.
The main difference between the registered high dose IC blockade (i.e. 3 mg/kg or 10 mg/kg) and our low dose IC blockade (using 0.3 mg/kg) is that only the higher ipilimumab doses were sufficient to translate into an objective response (Wolchok et al., Lancet Oncol, 11, 155-164 (2010)). One recognizes of course that with a higher dose there was a statistically significant trend, indicating a higher best objective response rate (Robert et al., Oncologist., 14, 848-861 (2009)); similarly, patients who received more therapy did better, but had therefore increased risk of developing irAEs. With low dose IC blockade (0.3 mg/kg) no grade 3-4 immune-related adverse events were reported. The appearance of mild-to-moderate immune-related events suggested a biological effect of ipilimumab extending the expiration date of T cells that was however insufficient to translate into an objective response. The latter is achieved with high dose (HD) IL-2 stimulation therapy, which complements the low dose IC blockade. Hyperthermia improves antitumor immune responses by activation of antigen-presenting cells and changes in lymphocyte trafficking.
The first case report describes a stage IV female TNBC patient with far advanced bilateral pulmonary metastasis who exhausted all conventional treatment. However, she went into nearly complete remission with low-dose IC blockade in combination with HD IL-2 treatment under Taurolidine protection and locoregional- and whole body hyperthermia but without classical chemotherapy. This case unexpectedly demonstrates that the liberated autoimmune forces can indeed be safely and effectively harnessed by dose adjustments of the IC blockade.
Breast cancers that lack estrogen receptor (ER) and progesterone receptor (PR) and demonstrate no over expression of human epidermal growth factor receptor 2 (HER2) are referred to as triple-negative breast cancer (TNBC). These tumors belong to the so called basal-like genomic subgroup and have poorer prognosis than the major breast cancer sub-types (Boyle, Annals of Oncology, 23, vi7-vi12 (2012)) (Kassam et al., Clin Breast Cancer, 9, 29-33 (2009)) (Perou et al., Nature, 406, 747-752 (2000)). Based on clinical experience many women with TNBC relapse more frequently and earlier than other subtypes, and continue to progress on administered first-, second-, and third-line palliative chemotherapy. TNBC also have a more aggressive course with shorter disease-free survival and overall survival (OS) times than other breast cancers (Perou et al., Nature, 406, 747-752 (2000)) (Sorlie et al., Proc Natl. Acad. Sci U.S.A, 100, 8418-8423 (2003)). Patients with TNBC have an increased likelihood of distant recurrence, a predilection for visceral, as opposed to bony, sites of relapse and death within 5 years of diagnosis (Andre et al., Ann Oncol, 23 Suppl 6, vi46-vi51 (2012)) (Anders et al., Clin Breast Cancer, 9 Suppl 2, S73-S81 (2009)). Due to the lack of specific targeted therapies increasing interest has been generated in novel treatment strategies in the metastatic setting, which would be essential to improve the survival of this high-risk subgroup (Lehmann et al., J Clin Invest, 121, 2750-2767 (2011)).
The HD IL-2 treatment—typically intravenous bolus of 600,000 or 720,000 Units/kg every 8 hours up to a maximum of 14-15 doses subject to toxicity—was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) often durable for decades without further therapy (Dutcher et al., Journal for Immunotherapy of Cancer, 2, 1-23 (2014)). Twenty years of evolution has led to a plethora of effective management approaches as how to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. IL-2 results in a cascade of cytokines released at supra-physiologic levels (‘cytokine storm’) from IL-2-activated T cells resulting in a well-described vascular leak syndrome (VLS) and eventual end-organ dysfunction.
Both preclinical and clinical data have demonstrated improved antitumor immune responses with the addition of mild hyperthermia. Its molecular mechanisms include the generation of heat shock proteins (Hsps), the activation of antigen-presenting cells and changes in lymphocyte trafficking. In addition, mild, fever range (40° C.) prolonged whole body hyperthermia may help reducing interstitial pressure in the tumor microenvironment (Skitzki et al., Curr Opin Investig. Drugs, 10, 550-558 (2009)) (Repasky et al., Cancer Immunol Res, 1, 210-216 (2013)) (Sen et al., Cancer Res, 71, 3872-3880 (2011)).